Aminocarbonylcarbamate compounds

ABSTRACT

The present disclosure provides a compound represented by Formula (I) and a pharmaceutically acceptable salt which are effective as a dopamine reuptake inhibitor and a method of using the compound: 
     
       
         
         
             
             
         
       
         
         
           
             wherein X is independently halo, alkyl, alkoxy or nitro; m is 0, 1, 2, 3 or 4; n is 1 or 2; R 1  and R 2  are independently H— or alkyl; R 3  is H—, alkyl or aralkyl; and R 4  is H— or aryl.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a non-provisional application of ProvisionalApplication No. 61/946,142, filed on 28 Feb. 2014. The entire disclosureof the application identified in this paragraph is incorporated hereinby reference.

FIELD

The present disclosure generally relates to a compound having inhibitoryactivity, pharmaceutical compositions comprising the compound, methodsof using the compound for treating diseases and processes for preparingthe same. More particularly, the present disclosure relates toaminocarbonylcarbamate compounds and pharmaceutically acceptable saltsthereof useful as dopamine reuptake inhibitor and/or a psycho-stimulant.

BACKGROUND

Dopamine is a monoamine neurotransmitter that plays a critical role inthe function of the hypothalamic-pituitary-adrenal axis and in theintegration of information in sensory, limbic, and motor systems. Theprimary mechanism for termination of dopamine neurotransmission isthrough reuptake of released dopamine by Na⁺/Cl⁻-dependent plasmamembrane transporter (Hoffman et al., 1998, Front. Neuroendocrinol.19(3):187-231). Depending on the surrounding ionic conditions, thedopamine transporter can function as a mediator of both inward directeddopamine transport (i.e., “reuptake”) and outward directed dopaminetransport (i.e., “release”). The functional significance of the dopaminetransporter is its regulation of dopamine neurotransmission byterminating the action of dopamine in a synapse via reuptake (Hitri etal., 1994, Clin. Pharmacol. 17:1-22)

The outcome of inhibiting dopamine reuptake is an increase in theconcentration of dopamine and of 3-methoxytyramine (3MT) in the synapticspace without modifying the concentrations of 3,4-dihydroxyphenylaceticacid (DOPAC) and of homovanillic acid (HVA). This property manifestsitself in an increase in the functioning of the central dopaminergicpathways, which is appraised objectively by behavioral modificationssuch as the appearance of stereotyped movements, an increase inlocomotor activity and a reduction in the period of immobility inanimals subjected to the test of “behavioral despair.”

As a result of their properties of inhibition of dopamine reuptake, thecompounds may be used in various indications including a hyperkineticdisorder such as attention deficit hyperactivity disorder (ADHD).

These indications, in many cases, involve a deficiency of functioning ofthe central dopaminergic systems. Therefore, dopamine reuptakeinhibition can lead to economical use of the synthesized/releaseddopamine which may result in an improvement in dopaminergictransmissions.

The tenth edition of the International Statistical Classification ofDiseases and Related Health Problems (ICD-10), 2010 providesclassifications of mental and behavioral disorders in Chapter V in whichsigns of ADHD are classified under “hyperkinetic disorders.”Hyperkinetic disorders are defined therein as a group of disorderscharacterized by an early onset, lack of persistence in activities thatrequire cognitive involvement, and a tendency to move from one activityto another without completing any one, together with disorganized,ill-regulated, and excessive activity. Hyperkinetic disorders (F90)include the following sub-classes of disorders:

F90.0 Disturbance of activity and attention,

F90.1 Hyperkinetic conduct disorder

F90.8 Other hyperkinetic disorders

F90.9 Hyperkinetic disorder, unspecified.

Phenylethylamine derivatives are a class of therapeutical medicinesuseful for managing central nervous system (CNS) diseases.

For example, U.S. Pat. Nos. 5,705,640 and 5,756,817 describe thatcarbamate compounds represented by the following formula are effectivein treating CNS disorders.

U.S. Pat. No. 5,077,289 mentions aminocarbonylcarbamate compounds usefulfor enhancing cholinergic functions and as analgesic agents.

SUMMARY

The present disclosure provides a novel compound represented by Formula(I) and a pharmaceutical acceptable salt thereof:

wherein:

X is independently halo, alkyl, alkoxy or nitro;

m is 0, 1, 2, 3 or 4

n is 1 or 2;

R₁ and R₂ are independently H— or alkyl;

R₃ is H—, alkyl or aralkyl; and

R₄ is H— or aryl,

wherein at least one of R₁, R₂, R₃ and R₄ is not H—.

The compounds of Formula (I) are useful in inhibiting dopamine reuptake.

In some embodiments, a compound of Formula (I) is selected from acompound of Formula (II) and a pharmaceutical acceptable salt thereof:

wherein X, m, n, R₁, R₂, and R₄ are as defined above.

In some embodiments, a compound of Formula (I) is selected from acompound of Formula (III) and a pharmaceutical acceptable salt thereof:

wherein X, m, n, R₁, R₂, and R₃ are as defined above.

In another embodiment, there is provided a pharmaceutical compositioncomprising a therapeutically effective amount of one or more compoundsdescribed herein and a pharmaceutically acceptable carrier.

In yet another embodiment, there is provided a method of treatingdopamine reuptake-related diseases in a mammal in need thereof byadministering a therapeutically effective amount of the compoundrepresented by Formula (I), (II) or (III). In an embodiment, thedopamine reuptake-related disease is attention deficit hyperactivitydisorder (ADHD).

DETAILED DESCRIPTION

The following description is merely exemplary in nature and is notintended to limit the present disclosure, application, or uses.

DEFINITIONS

“Alkoxy” is RO— where R is alkyl. Non-limiting examples of alkoxy groupsinclude methoxy, ethoxy and propoxy.

“Alkyl” refers to a straight or branched chain saturated hydrocarbylgroup. In an embodiment, alkyl has from 1 to 12 carbon atoms. In someembodiments, alkyl is a C₁-C₁₀ alkyl group or a C₁-C₄ alkyl group.Examples of alkyl groups include, but are not limited to, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl,octyl, nonyl and decyl.

“Aryl” refers to a monocyclic, bicyclic, or tricyclic carbon ring,wherein at least one ring is aromatic. In an embodiment, aryl has from 6to 12 carbon atoms. In some embodiments, aryl is a C₆-C₁₀ aryl group.

“Aralkyl” refers to an alkyl group substituted with an aryl group.

“Halo” refers to chloro (—Cl), bromo (—Br), fluoro (—F) or iodo (—I).

“Pharmaceutically acceptable” means suitable for use in pharmaceuticalpreparations, generally considered as safe for such use, officiallyapproved by a regulatory agency of a national or state government forsuch use, or being listed in the U.S. Pharmacopoeia or other generallyrecognized pharmacopoeia for use in animals, and more particularly inhumans.

“Pharmaceutically acceptable carrier” refers to a diluent, adjuvant,excipient, or carrier that alone or together provides a carrier orvehicle with which a compound or compounds of the disclosure isformulated and/or administered, and in which every ingredient or thecarrier as a whole is pharmaceutically acceptable.

“Pharmaceutically acceptable salt” refers to a salt which may enhancedesired pharmacological activity. Examples ofpharmaceutically-acceptable salts include acid addition salts formedwith inorganic or organic acids, metal salts and amine salts. Examplesof acid addition salts formed with inorganic acids include salts withhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid andphosphoric acid. Examples of acid addition salts formed with organicacids such as acetic acid, propionic acid, hexanoic acid, heptanoicacid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lacticacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid,o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethane-sulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methyl-bicyclo[2.2.2]oct-2-enel-carboxylic acid, gluco-heptonic acid,4,4′-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid,trimethyl-acetic acid, tertiary butylacetic acid, lauryl sulfuric acid,gluconic acid, glutamic acid, hydroxy-naphthoic acids, salicylic acid,stearic acid and muconic acid. Examples of metal salts include saltswith sodium, potassium, calcium, magnesium, aluminum, iron, and zincions. Examples of amine salts include salts with ammonia and organicnitrogenous bases strong enough to form salts with carboxylic acids.

“Therapeutically effective amount” refers to an amount of a compoundthat, when administered to a subject for treating a disease, issufficient to effect treatment for the disease. “Therapeuticallyeffective amount” can vary depending on the compound, the disease andits severity, the age, the weight, etc. of the subject to be treated.

Embraced herein, where applicable, are permissible isomers such astautomers, racemates, enantiomers, diastereomers, atropisomers, andisotopic variants. In various embodiments, the compounds of Formula (I)are enantiomers.

Compounds

This disclosure provides a compound represented by Formula (I) and apharmaceutical acceptable salt:

wherein:

X is independently halo, alkyl, alkoxy or nitro;

m is 0, 1, 2, 3 or 4;

n is 1 or 2;

R₁ and R₂ are independently H— or alkyl;

R₃ is H—, alkyl or aralkyl; and

R₄ is H— or aryl,

wherein at least one of R₁, R₂, R₃ and R₄ is not H—.

In an embodiment, X is halo, C₁-C₄ alkyl, C₁-C₄ alkoxy or nitro; R₁ andR₂ are independently H— or C₁-C₄ alkyl; R₃ is H—, C₁-C₄ alkyl or C₆-C₁₀aryl-C₁-C₄ alkyl; and R₄ is H— or C₆-C₁₀ aryl.

X is one or more substituents attached to the phenyl group of Formula(I) where m is a number of X substitutions. Thus, the phenyl group hasup to 4 substituents selected from X. In an embodiment, X isindependently selected from halo, methyl, tert-butyl, ethoxy and nitro.

n represents a number of carbon atom(s) of the alkylene linker; in otherwords, n=1 and n=2 represent —CH₂— and —CH₂CH₂—, respectively.

In an embodiment, R₁ and R₂ are independently H—, methyl or isopropyl.

In an embodiment, R₃ is methyl, ethyl or benzyl. In a particularembodiment, R₃ is methyl.

In an embodiment, R₄ is H— or phenyl. In a particular embodiment, R₄ isH—.

In particular embodiments, compounds of Formula (I) include, but notlimited to, the following compounds.

-   2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(3-chlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(4-tert-butylphenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(2-fluorophenyl)propyl (aminocarbonyl)carbamate;-   2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   2-amino-3-phenylpropyl (aminocarbonyl)benzylcarbamate;-   2-amino-3-phenylpropyl (aminocarbonyl)ethylcarbamate;-   2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-fluorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-methylphenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-ethoxyphenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-4-phenylbutyl (aminocarbonyl)methylcarbamate; and-   2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.

Compounds of Formula (I) include all permissible isomers such asracemates, enantiomers, diastereomers and isotopic variants. In someembodiments, a compound of Formula (I) is a stereoisomer. In aparticular embodiment, the stereoisomer is substantially enantiopure,for example consisting essentially of the R enantiomer of the compound.Examples of enantiomeric compounds include, but are not limited to, thefollowing compounds:

-   (2R)-2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   (2R)-2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   (2R)-2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;-   (2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   (2R)-2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   (2R)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   (2R)-2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   (2R)-2-(dimethylamino)-3-phenylpropyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-phenylpropyl (aminocarbonyl)benzylcarbamate;-   (2R)-2-amino-3-phenylpropyl (aminocarbonyl)ethylcarbamate;-   (2R)-2-amino-3-(2-chlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-chlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(2,4-dichlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(3,4-dichlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2S)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-methylphenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-ethoxyphenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-4-phenylbutyl (aminocarbonyl)methylcarbamate; and-   (2R)-2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.

In another embodiment, there is provided a compound of Formula (II) or apharmaceutically acceptable salt thereof:

wherein X, m, n, R₁, R₂, and R₄ are as defined above and at least one ofR₁, R₂ and R₄ is not H—.

In an embodiment, X is halo, C₁-C₄ alkyl, C₁-C₄ alkoxy or nitro; R₁ andR₂ are independently H— or C₁-C₄ alkyl; and R₄ is H— or C₆-C₁₀ aryl.

In an embodiment, X is independently halo, methyl, tert-butyl, ethoxy ornitro. In a particular embodiment, X is chloro, fluoro, methyl,tert-butyl, ethoxy or nitro.

In an embodiment, R₁ and R₂ are independently H—, methyl or isopropyl.In particular embodiments, R₁ is methyl and R₂ is H—; R₁ is methyl andR₂ is methyl; or R₁ is isopropyl and R₂ is H—.

In an embodiment, R₄ is H— or phenyl.

Examples of Formula (II) includes, but are not limited to, the followingcompounds:

-   2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(3-chlorophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(4-tert-butylphenyl)propyl (aminocarbonyl)carbamate;-   2-amino-3-(2-fluorophenyl)propyl (aminocarbonyl)carbamate;-   2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate; and-   2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.

Compounds of Formula (II) include all permissible isomers. In someembodiment, a compound of Formula (II) is an enantiomer. In a particularembodiment, the stereoisomer is substantially enantiopure, for exampleconsisting essentially of the R enantiomer of the compound. Examples ofenantiomers include, but are not limited to, the following compounds:

-   (2R)-2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   (2R)-2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;-   (2R)-2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;-   (2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   (2R)-2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;-   (2R)-2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate; and-   (2R)-2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.

In yet another embodiment, there is provided a compound of Formula (III)or a pharmaceutically acceptable salt thereof:

wherein X, m, n, R₁, R₂, and R₃ are as defined above at least one of R₁,R₂ and R₃ is not H—.

In an embodiment, X is halo, C₁-C₄ alkyl, C₁-C₄ alkoxy or nitro; R₁ andR₂ are independently H— or C₁-C₄ alkyl; and R₃ is H—, C₁-C₄ alkyl orC₆-C₁₀ aryl-C₁-C₄ alkyl.

In an embodiment, X is independently halo, methyl, tert-butyl, ethoxy ornitro. In a particular embodiment, X is chloro, fluoro, methyl,tert-butyl, ethoxy or nitro.

In an embodiment, R₁ and R₂ are independently H—, methyl or isopropyl.

In an embodiment, R₃ is H—, C₁-C₄ alkyl or C₆-C₁₀ aryl-C₁-C₄ alkyl,particularly methyl, ethyl or benzyl. In a particular embodiment, R₃ ismethyl.

Examples of Formula (III) includes, but are not limited to, thefollowing compounds:

-   2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   2-amino-3-phenylpropyl (aminocarbonyl)benzylcarbamate;-   2-amino-3-phenylpropyl (aminocarbonyl)ethylcarbamate;-   2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-fluorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-methylphenyl)propyl (aminocarbonyl)methylcarbamate;-   2-amino-3-(4-ethoxyphenyl)propyl (aminocarbonyl)methylcarbamate; and-   2-amino-4-phenylbutyl (aminocarbonyl)methylcarbamate.

Compounds of Formula (III) include all permissible isomers. In someembodiment, a compound of Formula (III) is an enantiomer. In aparticular embodiment, the stereoisomer is substantially enantiopure,for example consisting essentially of the R enantiomer of the compound.Examples of enantiomers include, but are not limited to, the followingcompounds:

-   (2R)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   (2R)-2-(dimethylamino)-3-phenylpropyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-phenylpropyl (aminocarbonyl)benzylcarbamate;-   (2R)-2-amino-3-phenylpropyl (aminocarbonyl)ethylcarbamate;-   (2R)-2-amino-3-(2-chlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-chlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(2,4-dichlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(3,4-dichlorophenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2S)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-methylphenyl)propyl    (aminocarbonyl)methylcarbamate;-   (2R)-2-amino-3-(4-ethoxyphenyl)propyl    (aminocarbonyl)methylcarbamate; and-   (2R)-2-amino-4-phenylbutyl (aminocarbonyl)methylcarbamate.

In yet another embodiment, there is provided 2-amino-3-phenylpropyl(aminocarbonyl)carbamate or a pharmaceutically acceptable salt thereof.In some embodiment, the compound is an enantiomer of2-amino-3-phenylpropyl (aminocarbonyl)carbamate, such as,(2R)-2-amino-3-phenylpropyl (aminocarbonyl)carbamate.

Synthesis of Compounds

In some embodiments, the compounds of Formula (I) can be prepared by thesynthetic method of Scheme I or II, as described below.

It should be noted that the stereochemistry of the final products (I)depend solely on that of the starting material (II); a starting material(II) with an S-enantiomer yields only a product with S-enantiomer (I)and a starting material (II) with an R-enantiomer yields only a productwith R-enantiomer (I).

When R₃ and R₄ are H—, the desired compound may be prepared by thesynthetic method described in Scheme I:

As shown in Scheme I, 2-amino-3-phenylpropan-1-ol (II) is reacted withsodium cyanate and methansulfonic acid in dichloromethane, to give2-amino-3-phenylpropyl (aminocarbonyl)carbamate (III).

Details of the reaction conditions described in Scheme I are as follows.For the conversion of the compounds (II) to the compound (III), theconcentration of the starting material (II) is between about 0.05 to 0.1mole with sodium cyanate from about 6 equivalents and methanesulfonicacid from about 7 equivalents. This reaction is preferably carried outin dichloromethane at a temperature of 0° C. to room temperature.

In the Scheme I, HX represents an acid capable of forming apharmacologically useful salt with the basic nitrogen atom. Specificexamples of the anhydrous acid used for the preparation of the compound(IV) from the compound (III) include hydrochloric acid, sulfuric acid,phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid,salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid,tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid,aspartic acid, benzene sulfonic acid, methane sulfonic acid, ethanesulfonic acid, hydroxymethane sulfonic acid and hydroxyethane sulfonicacid and the like. Additional acids can refer to “Pharmaceutical Salts”,J. Pharm. Sci., 1977; 66(1): 1-19. This preparation is executed in areaction media which can be exemplified by an ethereal solvent such asTHF, an alcoholic solvent such as methanol, an ester solvent such asethyl acetate, and aromatic solvent, and any compositional mixturethereof. An ethereal solvent is recommended as an addition solution,including ethyl ether, propyl ether, isopropyl ether, butyl ether,isobutyl ether.

When R₃ is not H— and R₄ is H—, the desired compound may be prepared bythe synthetic method described in Scheme II:

As shown in Scheme II, 2-amino-3-phenylpropyl carbamate (V) is reactedwith sodium cyanate and methansulfonic acid in dichloromethane, to give2-amino-3-phenylpropyl (aminocarbonyl)carbamate (VI).

Details of the reaction conditions described in Scheme II are asfollows. For the conversion of the compounds (V) to the compound (VI),the concentration of the starting material (II) is between about 0.05 to0.1 mole with sodium cyanate from about 4 equivalents andmethanesulfonic acid from about 5 equivalents. This reaction ispreferably carried out in dichloromethane at a temperature of 0° C. toroom temperature.

In the Scheme II, HX represents an acid capable of forming apharmacologically useful salt with the basic nitrogen atom.

When R₃ and R₄ are not H—, the desired compound may be prepared by thesynthetic method described in Scheme III:

As shown in Scheme III, 2-amino-3-phenylpropyl carbamate (V) is reactedwith and isocyanate of the formula R₄NCO to give 2-amino-3-phenylpropyl(aminocarbonyl)carbamate (VIII).

Details of the reaction conditions described in Scheme III are asfollows. For the conversion of the compounds (V) to the compound (VIII),the concentration of the starting material (II) is between about 0.05 to0.1 moles with isocyanate, R₄NCO from about 6 equivalents andmethanesulfonic acid from about 3 equivalents. This reaction ispreferably carried out in dichloromethane at a temperature of 0° C. toroom temperature.

In the Scheme III, HX represents an acid capable of forming apharmacologically useful salt with the basic nitrogen atom.

Pharmaceutical Compositions

In one embodiment, there is provided a pharmaceutical compositioncomprising, in addition to one or more compounds described herein, apharmaceutically acceptable carrier. In various embodiments, the carriercomprises a diluent, adjuvant, excipient, other additive, or acombination of additive that separately or together provide a carrier inwhich the compositions can be formulated or administered. Thecomposition can take any suitable form for the desired route ofadministration. Where the composition is to be administered orally, anysuitable orally deliverable dosage form can be used, including, withoutlimitation, tablets, capsules (solid- or liquid-filled), powders,granules, syrups and other liquids, elixirs, inhalants, troches,lozenges, and solutions. Injectable compositions or iv infusions arealso provided in the form of solutions, suspensions, and emulsions.

In particular embodiments, the pharmaceutical composition is an oralformulation. Since the compounds of Formula I absorb well orally, it isgenerally unnecessary to resort to parenteral administration. For oraladministration, the compound is preferably formulated with apharmaceutically acceptable carrier. The ratio of the carrier to thecompound would not be critical to the pharmacological effects of theformulation, and the ratio can vary considerably depending onformulating conditions. In tableting, various edible pharmaceuticalcarriers or the mixture thereof can be included therein. A suitablecarrier, for example, is a mixture of lactose, dibasic calcium phosphateand/or corn starch. Other pharmaceutically acceptable ingredients can befurther added, including lubricants such as magnesium stearate.

A pharmaceutical composition according to the present disclosure maycontain one or more additional therapeutic agents, for example, toincrease the efficacy or decrease the side effects. In an embodiment,the pharmaceutical composition includes one or more active ingredientseffective to treat ADHD such as Adderall, Concerta, Dexedrine, Focalin,Metadate, Methylin, Ritalin, Vyvanse, Daytrana, and Quillivant.

Medical Utilities

Yet another aspect of the present disclosure is to provide a method ofinhibiting or treating dopamine reuptake-related diseases in animal,comprising administering to said animal a therapeutically effectiveamount of one or more compounds of Formula (I) and salts thereof. Thedopamine reuptake-related diseases include, for example, hyperkineticdisorders such as ADHD. In one embodiment, the method of inhibiting ortreating disease comprises administering to an animal a pharmaceuticalcomposition comprising an effective amount of one or more compounds ofFormula (I) and a pharmaceutically-acceptable carrier.

A method of the present disclosure is particularly suitable for use withhumans, but may be used with other animals, particularly mammals.

In ADHD therapies, psychostimulants reduce excess motor activity andenhance concentration. The reduction in physical activity in ADHDpatients after psychostimulant treatment is supported by studies usingsubjective rating scales and objective measures such as actometers,respiration calorimetry and microwave motor activity detectors.

Primary treatment for ADHD is administration of stimulant medication,and research has focused on dopamine control. Imaging experiments haveidentified dopamine transporters predominantly in the caudatoputamen asmethylphenidate's site of action. Single-photon emission computedtomography (SPECT) and positron emission tomography (PET) studies inADHD patients have also demonstrated decreased metabolic activities inthe basal ganglia, a region that contains high concentrations ofdopamine and dopamine receptors. Assessments of catecholaminemetabolites in cerebral spinal fluid of ADHD children support theimaging studies, demonstrating a positive correlation between thedopamine metabolite homovanillic acid and the degree of hyperactivity.Central dopaminergic activity is critical to the functioning of bothmotor and cognitive systems.

In therapeutic use as a dopamine reuptake inhibitor, the compounds ofthe present disclosure, alone or in combination with pharmaceuticallyacceptable carrier, are administered to patients at a dosage of from 0.7to 7,000 mg per day. For a normal human adult with a body weight ofapproximately 70 kg, the administration amount is translated into adaily dose of 0.01 to 100 mg per kg of body weight. The specific dosageemployed, however, may vary depending upon the requirements of thepatient, the severity of patient's condition and the activity of thecompound. The determination of optimum dosages for a particularsituation must clinically be done and is within the skill of the art.

A better understanding of the present invention may be obtained in lightof following examples which are set forth to illustrate, but are not tobe construed to limit, the present invention.

EXAMPLE Example 1 2-Amino-3-phenylpropyl (aminocarbonyl)carbamate andhydrochloride salt thereof

2-Amino-3-phenylpropan-1-ol (1.984 mmol) was dissolved indichloromethane and methansulfonic acid (0.9 ml, 7 eq) and sodiumcyanate (774 mg, 6 eq) was added in an ice bath. The resulting reactionmixture was stirred for 1 day. Water was added to terminate the reactionand the reaction mixture was neutralized to pH 7-8 with 1N NaOHsolution. The organic layer was extracted 3 times with dichloromethane,dried over magnesium sulfate and concentrated in vacuo, to give oil.This was dissolved in dichloromethane and the solution was treated witha solution of HCl in ethyl ether. The resulting precipitate was filteredto give 2-amino-3-phenylpropyl (aminocarbonyl)carbamate; hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.79 (br, 1H), 8.26 (br, 3H), 7.33 (m, 5H),7.18 (br, 2H), 4.19 (m, 1H), 3.98 (m, 1H), 3.68 (m, 1H), 2.93 (m, 2H)

Example 2 (2R)-2-Amino-3-phenylpropyl (aminocarbonyl)carbamate andhydrochloride salt thereof

The procedure given in Example 1 was followed using(2R)-2-amino-3-phenylpropan-1-ol as a reactant, instead of2-amino-3-phenylpropan-1-ol, to give (2R)-2-amino-3-phenylpropyl(aminocarbonyl)carbamate; hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.82 (br, 1H), 8.19 (br, 3H), 7.33 (br, 5H),7.17 (br, 2H), 4.18 (m, 1H), 3.97 (m, 1H), 3.65 (m, 1H), 2.94 (m, 2H)

Example 3 (2R)-2-(Isopropylamino)-3-phenylpropyl(aminocarbonyl)carbamate and hydrochloride salt thereof

The procedure given in Example 1 was followed using(2R)-2-(isopropylamino)-3-phenylpropan-1-ol as a reactant, instead of2-amino-3-phenylpropan-1-ol, to give(2R)-2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.87 (s, 1H), 9.64 (br, 1H), 9.10 (br, 1H),7.33 (m, 5H), 7.16 (br, 2H), 4.25 (dd, 1H), 4.04 (dd, 1H), 3.67 (br,1H), 3.51 (br, 1H), 2.92 (dd, 1H), 2.49 (dd, 1H), 1.25 (s, 6H).

Example 4 (2R)-2-(Dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamateand hydrochloride salt thereof

The procedure given in Example 1 was followed using(2R)-2-(dimethylamino)-3-phenylpropan-1-ol as a reactant, instead of2-amino-3-phenylpropan-1-ol, to give(2R)-2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 11.29 (br, 1H), 10.05 (s, 1H), 7.34 (m, 5H),7.23 (br, 2H), 4.33 (dd, 1H), 3.99 (dd, 1H), 3.84 (br, 1H), 3.41 (s,6H), 2.97 (dd, 1H), 2.94 (dd, 1H).

Example 5 (2R)-2-Amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamateand hydrochloride salt thereof

The procedure given in Example 1 was followed using(2R)-2-amino-3-(2-chlorophenyl)propan-1-ol.HCl as a reactant, instead of2-amino-3-phenylpropan-1-ol, to give(2R)-2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.71 (br, 1H), 8.50 (br, 3H), 7.48 (m, 2H),7.34 (m, 2H), 7.15 (br, 2H), 4.22 (m, 1H), 4.02 (m, 1H), 3.70 (m, 1H),3.14 (m, 2H)

Example 6 (2R)-2-Amino-3-(2,4-dichlorophenyl)propyl(aminocarbonyl)carbamate and hydrochloride salt thereof

The procedure given in Example 1 was followed using(2R)-2-amino-3-(2,4-dichlorophenyl)propan-1-ol.HCl as a reactant,instead of 2-amino-3-phenylpropan-1-ol, to give(2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;hydrochloride

1H-NMR (DMSO-d6, 200 MHz) δ 9.82 (br, 1H), 8.23 (br, 3H), 7.66 (s, 1H),7.49 (m, 2H), 7.18 (br, 2H), 4.26 (m, 1H), 4.00 (m, 1H), 3.64 (m, 1H),3.09 (m, 2H)

Example 7 (2R)-2-Amino-3-(3,4-dichlorophenyl)propyl(aminocarbonyl)carbamate; hydrochloride

The procedure given in Example 1 was followed using(2R)-2-amino-3-(3,4-dichlorophenyl)propan-1-ol.HCl as a reactant,instead of 2-amino-3-phenylpropan-1-ol, to give(2R)-2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;hydrochloride

1H-NMR (DMSO-d6, 200 MHz) δ 9.82 (br, 1H), 8.25 (br, 3H), 7.65 (s, 1H),7.62 (d, 1H), 7.34 (d, 1H), 7.18 (br, 2H), 4.26 (m, 1H), 4.00 (m, 1H),3.72 (m, 1H), 2.96 (m, 2H)

Example 8 (2R)-2-Amino-3-phenylpropyl (aminocarbonyl)methylcarbamate andhydrochloride salt thereof

(2R)-2-amino-3-phenylpropyl methylcarbamate (11.932 mmol) was dissolvedin dichloromethane and methansulfonic acid (3.1 ml, 4 eq) and sodiumcyanate (5.39 g, 3 eq) was added in an ice bath. The resulting reactionmixture was stirred for 1 day. Water was added to terminate the reactionand the reaction mixture was basicified to pH8-9 with 1N NaOH solution.The organic layer was extracted 3 times with dichloromethane, dried overmagnesium sulfate and concentrated in vacuo, to give oil. This wasdissolved in dichloromethane and the solution was treated with asolution of HCl in ethyl ether. The resulting precipitate was filteredto give (2R)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;hydrochloride

1H-NMR (DMSO-d6, 200 MHz) δ 8.55 (br, 3H), 7.84 (br, 1H), 7.32 (m, 6H),4.30 (dd, 1H), 4.06 (dd, 1H), 3.72 (m, 1H), 3.18 (dd, 1H), 3.14 (s, 3H),2.90 (dd, 1H)

Example 9 2-Amino-3-(4-chlorophenyl)propyl(aminocarbonyl)carbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using2-amino-3-(4-chlorophenyl)propyl carbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.78 (br, 1H), 8.41 (br, 3H), 7.38 (m, 4H),7.16 (br, 2H), 4.23 (m, 1H), 3.99 (m, 1H), 3.62 (m, 1H), 2.96 (m, 2H)

Example 10 2-Amino-3-(3-chlorophenyl)propyl (aminocarbonyl)carbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using2-amino-3-(3-chlorophenyl)propyl carbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give2-amino-3-(3-chlorophenyl)propyl (aminocarbonyl)carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.82 (br, 1H), 8.20 (br, 3H), 7.37 (m, 6H),4.26 (m, 1H), 3.96 (m, 1H), 3.70 (m, 1H), 2.95 (m, 2H)

Example 11 2-Amino-3-(4-nitrophenyl)propyl(aminocarbonyl)carbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using2-amino-3-(4-nitrophenyl)propyl carbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give2-Amino-3-(4-nitrophenyl)propyl (aminocarbonyl)carbamate; hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.81 (br, 1H), 8.37 (br, 3H), 8.22 (d, 2H),7.63 (d, 2H), 7.18 (br, 2H), 4.24 (m, 1H), 4.03 (m, 1H), 3.75 (m, 1H),3.11 (m, 2H)

Example 12 2-Amino-3-(4-tert-butylphenyl)propyl(aminocarbonyl)carbamateand hydrochloride salt thereof

The procedure given in Example 8 was followed using2-amino-3-(4-tert-butylphenyl)propyl carbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give2-amino-3-(4-tert-butylphenyl)propyl (aminocarbonyl) carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.78 (br, 1H), 8.33 (br, 3H), 7.25 (m, 5H),4.21 (m, 1H), 3.99 (m, 1H), 3.60 (m, 1H), 2.92 (m, 2H), 1.27 (s, 9H)

Example 13 2-Amino-3-(2-fluorophenyl)propyl(aminocarbonyl)carbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using2-amino-3-(2-fluorophenyl)propyl carbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give2-amino-3-(2-fluorophenyl)propyl (aminocarbonyl)carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.77 (br, 1H), 8.34 (br, 3H), 7.26 (m, 6H),4.24 (dd, 1H), 4.01 (dd, 1H), 3.65 (m, 1H), 3.00 (m, 2H)

Example 14 (2R)-2-(Methylamino)-3-phenylpropyl(aminocarbonyl)carbamateand hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-(methylamino)-3-phenylpropyl carbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-(methylamino)-3-phenylpropyl (aminocarbonyl) carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 9.88 (br, 1H), 9.32 (br, 2H), 7.29 (m, 7H),4.32 (m, 1H), 3.96 (m, 1H), 3.66 (m, 1H), 3.20 (m, 1H), 2.91 (m, 1H),2.65 (s, 3H)

Example 15 (2R)-2-(Dimethylamino)-3-phenylpropyl(aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-(dimethylamino)-3-phenylpropyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-(dimethylamino)-3-phenylpropyl (aminocarbonyl) methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 11.20 (br, 1H), 7.82 (br, 1H), 7.34 (m, 6H),4.24 (m, 2H), 3.92 (m, 1H), 3.09 (s, 3H), 2.92 (m, 2H), 2.87 (s, 6H)

Example 16 (2R)-2-Amino-3-phenylpropyl (aminocarbonyl)benzylcarbamateand hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-phenylpropyl benzylcarbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-phenylpropyl (aminocarbonyl) benzylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.15 (br, 3H), 7.92 (br, 1H), 7.58 (br, 1H),7.28 (m, 8H), 6.93 (m, 2H), 5.03 (m, 2H), 4.22 (m, 1H), 3.89 (m, 1H),3.62 (m, 1H), 2.84 (m, 1H), 2.65 (m, 1H

Example 17 (2R)-2-Amino-3-phenylpropyl(aminocarbonyl)ethylcarbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-phenylpropyl ethylcarbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-phenylpropyl (aminocarbonyl)ethylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.31 (br, 3H), 7.80 (br, 1H), 7.31 (m, 6H),4.30 (m, 1H), 4.06 (m, 1H), 3.75 (m, 3H), 3.00 (m, 2H), 1.08 (t, 3H)

Example 18 (2R)-2-Amino-3-(2-chlorophenyl)propyl(aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-(2-chlorophenyl)propyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl) methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.54 (br, 3H), 7.80 (br, 1H), 7.40 (m, 6H),4.20 (m, 2H), 3.78 (m, 1H), 3.16 (m, 2H), 3.12 (s, 3H)

Example 192-Amino-3-(4-fluorophenyl)propyl(aminocarbonyl)methylcarbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using2-amino-3-(4-fluorophenyl)propyl methylcarbamate as a reactant, insteadof (2R)-2-amino-3-phenylpropyl methylcarbamate, to give2-amino-3-(4-fluorophenyl)propyl (aminocarbonyl)methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 7.10 (d, 2H), 6.92 (d, 2H), 6.01 (br, 2H),4.3 (d, 2H), 3.6 (dd, 1H), 3.16 (s, 3H), 2.77 (d, 2H), 2.0 (br, 2H).

Example 20 (2R)-2-Amino-3-(4-chlorophenyl)propyl (aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-(4-chlorophenyl)propyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl) methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 7.10 (d, 2H), 6.92 (d, 2H), 6.01 (br, 2H),4.3 (d, 2H), 3.6 (dd, 1H), 3.16 (s, 3H), 2.77 (d, 2H), 2.0 (br, 2H).

Example 21 (2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-(2,4-dichlorophenyl)propyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate; hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.52 (br, 3H), 7.82 (br, 1H), 7.64 (s, 1H),7.48 (m, 3H), 4.26 (m, 1H), 4.16 (m, 1H), 3.76 (m, 1H), 3.18 (m, 5H)

Example 22 (2R)-2-Amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-(3,4-dichlorophenyl)propyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate; hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.36 (br, 3H), 7.84 (br, 1H), 7.52 (m, 4H),4.20 (m, 2H), 3.82 (m, 1H), 3.14 (s, 3H), 3.09 (m, 2H)

Example 23 (2S)-2-Amino-3-phenylpropyl (aminocarbonyl)methylcarbamateand hydrochloride salt thereof

The procedure given in Example 8 was followed using(2S)-2-amino-3-phenylpropyl methylcarbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2S)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.55 (br, 3H), 7.84 (br, 1H), 7.32 (m, 6H),4.30 (dd, 1H), 4.06 (dd, 1H), 3.72 (m, 1H), 3.18 (dd, 1H), 3.14 (s, 3H),2.90 (dd, 1H)

Example 24 2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using2-amino-3-phenylpropyl methylcarbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate; hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.55 (br, 3H), 7.84 (br, 1H), 7.32 (m, 6H),4.30 (dd, 1H), 4.06 (dd, 1H), 3.72 (m, 1H), 3.18 (dd, 1H), 3.14 (s, 3H),2.90 (dd, 1H)

Example 25 (2R)-2-Amino-3-(4-nitrophenyl)propyl (aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-(4-nitrophenyl)propyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl) methylcarbamate;hydrochloride

1H-NMR (DMSO-d6, 200 MHz) δ 8.39 (br, 3H), 8.22 (d, 2H), 7.82 (br, 1H),7.62 (d, 2H), 7.46 (br, 1H), 4.32 (m, 1H), 4.16 (m, 1H), 3.84 (m, 1H),3.18 (m, 2H), 3.12 (s, 3H)

Example 26 (2R)-2-Amino-3-(4-methylphenyl)propyl (aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-(4-methylphenyl)propyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-(4-mehtylphenyl)propyl (aminocarbonyl) methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.34 (br, 3H), 7.82 (br, 1H), 7.42 (br, 1H),7.16 (s, 4H), 4.26 (m, 1H), 4.05 (m, 1H), 3.65 (m, 1H), 3.13 (s, 3H),3.04 (m, 1H), 2.82 (m, 1H), 2.28 (s, 3H)

Example 27 (2R)-2-Amino-3-(4-ethoxyphenyl)propyl (aminocarbonyl)methylcarbamate and hydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-3-(4-ethoxyphenyl)propyl methylcarbamate as a reactant,instead of (2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-3-(4-ethoxyphenyl)propyl (aminocarbonyl) methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.45 (br, 3H), 7.84 (br, 1H), 7.24 (br, 1H),7.19 (d, 2H), 6.89 (d, 2H), 4.26 (m, 1H), 4.01 (m, 3H), 3.66 (m, 1H),3.14 (s, 3H), 3.08 (m, 1H), 2.82 (m, 1H), 1.31 (t, 3H)

Example 28 (2R)-2-Amino-4-phenylbutyl (aminocarbonyl)methylcarbamate andhydrochloride salt thereof

The procedure given in Example 8 was followed using(2R)-2-amino-4-phenylbutyl methylcarbamate as a reactant, instead of(2R)-2-amino-3-phenylpropyl methylcarbamate, to give(2R)-2-amino-4-phenylbutyl (aminocarbonyl)methylcarbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 8.41 (br, 3H), 7.85 (br, 1H), 7.42 (br, 1H),7.27 (m, 5H), 4.42 (dd, 1H), 4.24 (dd, 1H), 3.42 (m, 1H), 3.14 (s, 3H),2.74 (t, 2H), 1.96 (m, 2H)

Example 29 (2R)-2-Amino-3-phenylpropyl (anilinocarbonyl)carbamate andhydrochloride salt thereof

(2R)-2-amino-3-phenylpropyl carbamate (2.397 mmol) was dissolved indichloromethane and methansulfonic acid (0.47 ml, 3 eq) and phenylisocyanate (1.56 ml, 6 eq) was added in an ice bath. The resultingreaction mixture was stirred for 1 day. Water was added to terminate thereaction and the reaction mixture was neutralized to pH 7-8 with 1N NaOHsolution. The organic layer was extracted 3 times with dichloromethane,dried over magnesium sulfate and concentrated in vacuo, to give oil.This was dissolved in dichloromethane and the solution was treated witha solution of HCl in ethyl ether. The resulting precipitate was filteredto give (2R)-2-amino-3-phenylpropyl (anilinocarbonyl)carbamate;hydrochloride.

1H-NMR (DMSO-d6, 200 MHz) δ 10.29 (br, 1H), 9.79 (br, 1H), 8.46 (br,3H), 7.34 (m, 10H), 4.32 (m, 1H), 4.05 (m, 1H), 3.70 (m, 1H), 3.04 (m,2H)

Example 30 Dopamine Transporter Binding Assay

Rats (SD-rat, Orient Korea, male, 200-250 g) were sacrificed bydecapitation. The striata were removed immediately and then stored at−80° C. until used. On the day of the manipulation, the striata werethawed and suspended in 20 volumes of buffer containing 50 mM Tris-HCland 120 mM NaCl (pH 7.7). The suspension then was centrifuged at 17,700rpm for 20 minutes. The pellet was resuspended in 20 volumes of thebuffer and centrifuged at 17,700 rpm for 20 minutes. This procedure wasrepeated once more. The pellet obtained was resuspended in a few ml ofthe buffer and then homogenized. The concentration of the receptorsource was determined by Lowry et al., 1951, J. Biol. Chem. 193:265-275.

Dopamine Transporter Assay Protocol

The dopamine reuptake transporter binding assay was performed accordingto the methods described in Madras et al., 1989, Mol. Pharmacol.36(4):518-524, and Javitch et al., 1984, Mol. Pharmacol. 26(1):35-44.The receptor source was rat striatal membranes; the radioligand wasGBR12935 [prolyene-2,3-³H] (DuPont-Nen, Boston, Mass.) (250 μCi), at 1.0nM of a final concentration; for non-specific binding1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazinedihydrochloride (GBR12909) (Research Biochemicals International, USA), ahigh-affinity dopamine uptake inhibitor, was used at 10 μM; referencecompound was nomifensine maleate (Research Biochemicals International,USA. Reactions were carried out in 50 mM Tis-HCl (pH 7.7), containing120 mM NaCl and at 25° C. for 45 minutes. Then the reaction wasterminated by rapid vacuum filtration onto glass fiber filters.Radioactivity trapped in the filters was measured and the specificinteractions of the test compound with the dopamine uptake site weredetermined compared to control values. The results are represented inTable 1.

TABLE 1 Example % inhibition (10 μM) Example 2 50.1% Example 3 40.1%Example 4 38.4% Example 6 20.4% Example 7 41.2% Example 8 20.3% Example9 42.8% Example 14 35.9% Example 15 55.5% Example 16 20.8% Example 1741.2% Example 18 17.5% Example 19 34.3% Example 21 31.5% Example 2237.0% Example 24 45.0% Example 29 50.7%

As described herein, the compounds of the present disclosure wereobserved to have binding affinity for dopamine transporter. The resultsindicate that the compounds can be useful to treat or inhibit diseasescaused by abnormal dopamine reuptake.

Example 31 Locomotor Activity Test

Psychostimulant activity was examined through the locomotor activitytest (LMA). The LMA is a behavioral test developed to predict theefficacy of psychostimulants. The LMA is an attractive test forpsychostimulants because it is sensitive and specific. All of the majorclasses of psychostimulants enhance ambulatory activities in the LMA,including methylphenidate, amphetamine, and many other psychostimulants.

Sixteen (16) mice (3 weeks CrjBgi:CD-1 (ICR) and 8 weeks C57BL/6) werepurchased from Orient Bio Inc. (Gyeonggi-do, Korea). The mice weredivided into a control group and a drug-treated group (eight (8) miceper group) by a block randomization method. Each of the group was placedin an empty cage and bred under environmental conditions of 19-25° C.with a relative humidity of 40-60% and a lighting cycle of 12 hrlight/12 hr dark. Diet and water were supplied ad libitum. After oneweek of acclimation, the LMA test was carried out. The mice werehabituated for over 1 hour in an LMA room before starting the LMA test.After habituation, the test compounds (10 or 30 mg/kg) were administeredto the drug-treated group by intraperitoneal injection. At 30 minutesafter i.p. dosing, LMA was measured using automated photobeams,Opto-Varimax® (Columbus Instruments, Ohio, US-

) and recorded on a computer. The total locomoter counts for each mousewere recorded for 10 minutes.

Statistical mean values for control and drug-treated groups werecalculated and the percent changes from control were determined. Percentchanges from control-revealed as % reduction-of some of the compounds ofthe instant disclosure are presented in Table 2.

TABLE 2 Example % ambulation Example 2 118.7% (30 mg/kg, ip) Example 3291.5% (30 mg/kg, ip) Example 4 242.6% (30 mg/kg, ip) Example 8 186.4%(30 mg/kg, ip) Example 15 202.2% (10 mg/kg, ip)

As described above, the compounds of the present disclosure wereobserved to have psychostimulant efficacy which is useful to treat adopamine reuptake-related disease such as ADHD.

What is claimed is:
 1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein X isindependently halo, alkyl, alkoxy or nitro; m is 0, 1, 2, 3 or 4 n is 1or 2; R₁ and R₂ are independently H— or alkyl; R₃ is H—, alkyl oraralkyl; and R₄ is H— or aryl, wherein at least one of R₁, R₂, R₃ and R₄is not H—.
 2. The compound or pharmaceutically acceptable salt of claim1, wherein X is halo, C₁-C₄ alkyl, C₁-C₄ alkoxy or nitro; R₁ and R₂ areindependently H— or C₁-C₄ alkyl; R₃ is H—, C₁-C₄ alkyl or C₆-C₁₀aryl-C₁-C₄ alkyl; and R₄ is H— or C₆-C₁₀ aryl.
 3. The compound orpharmaceutically acceptable salt of claim 1, which is selected from acompound of Formula (II):

wherein X is independently halo, alkyl, alkoxy or nitro; m is 0, 1, 2, 3or 4; n is 1 or 2; R₁ and R₂ are independently H— or alkyl; and R₄ is H—or aryl, wherein at least one of R₁, R₂ and R₄ is not H—.
 4. Thecompound or pharmaceutically acceptable salt according to claim 3,wherein X is H—, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy or nitro; R₁ and R₂ areindependently H— or C₁-C₄ alkyl; and R₄ is H— or C₆-C₁₀ aryl.
 5. Thecompound or pharmaceutically acceptable salt according to claim 3,wherein each X is independently halo, methyl, tert-butyl, ethoxy ornitro.
 6. The compound or pharmaceutically acceptable salt according toclaim 3, wherein R₁ and R₂ are independently H—, methyl or isopropyl. 7.The compound or pharmaceutically acceptable salt according to claim 3,wherein R₄ is H— or phenyl.
 8. The compound or pharmaceuticallyacceptable salt according to claim 3, wherein R₄ is H—.
 9. The compoundor pharmaceutically acceptable salt according to claim 3, wherein n is1, and R₄ are H—.
 10. The compound or pharmaceutically acceptable saltaccording to claim 3, which is selected from the group consisting of:2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)carbamate;2-amino-3-(3-chlorophenyl)propyl (aminocarbonyl)carbamate;2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)carbamate;2-amino-3-(4-tert-butylphenyl)propyl (aminocarbonyl)carbamate;2-amino-3-(2-fluorophenyl)propyl (aminocarbonyl)carbamate;2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate; and2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.
 11. The compound orpharmaceutically acceptable salt according to claim 3, wherein thecompound is a substantially pure stereoisomer.
 12. The compound orpharmaceutically acceptable salt according to claim 11, which isselected from the group consisting of:(2R)-2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;(2R)-2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;(2R)-2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;(2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;(2R)-2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;(2R)-2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate; and(2R)-2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.
 13. The compoundor pharmaceutically acceptable salt according to claim 1, wherein thesalt is hydrochloride.
 14. The compound or pharmaceutically acceptablesalt of claim 1, which is selected from a compound of Formula (III):

wherein X is independently halo, alkyl, alkoxy or nitro; m is 0, 1, 2, 3or 4; n is 1 or 2; R₁ and R₂ are independently H— or alkyl; and R₃ isH—, alkyl or aralkyl, wherein at least one of R₁, R₂ and R₃ is not H—.15. The compound or pharmaceutically acceptable salt according to claim14, wherein X is H—, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy or nitro; and R₁and R₂ are independently H— or C₁-C₄ alkyl.
 16. The compound orpharmaceutically acceptable salt according to claim 14, wherein each Xis independently halo, methyl, tert-butyl, ethoxy or nitro.
 17. Thecompound or pharmaceutically acceptable salt according to claim 14,wherein R₁ and R₂ are independently H—, methyl or isopropyl.
 18. Thecompound or pharmaceutically acceptable salt according to claim 14,wherein R₃ is C₁-C₄ alkyl or C₆-C₁₀ aryl-C₁-C₄ alkyl.
 19. The compoundor pharmaceutically acceptable salt according to claim 14, wherein R₃ ismethyl, ethyl or benzyl.
 20. The compound or pharmaceutically acceptablesalt according to claim 14, wherein n is 1 and R₃ is H—.
 21. Thecompound or pharmaceutically acceptable salt according to claim 14,which is selected from the group consisting of: 2-amino-3-phenylpropyl(aminocarbonyl)methylcarbamate; 2-(dimethylamino)-3-phenylpropyl(aminocarbonyl)methylcarbamate; 2-amino-3-phenylpropyl(aminocarbonyl)benzylcarbamate; 2-amino-3-phenylpropyl(aminocarbonyl)ethylcarbamate; 2-amino-3-(2-chlorophenyl)propyl(aminocarbonyl)methylcarbamate; 2-amino-3-(4-fluorophenyl)propyl(aminocarbonyl)methylcarbamate; 2-amino-3-(4-chlorophenyl)propyl(aminocarbonyl)methylcarbamate; 2-amino-3-(2,4-dichlorophenyl)propyl(aminocarbonyl)methylcarbamate; 2-amino-3-(3,4-dichlorophenyl)propyl(aminocarbonyl)methylcarbamate; 2-amino-3-(4-nitrophenyl)propyl(aminocarbonyl)methylcarbamate; 2-amino-3-(4-methylphenyl)propyl(aminocarbonyl)methylcarbamate; 2-amino-3-(4-ethoxyphenyl)propyl(aminocarbonyl)methylcarbamate; and 2-amino-4-phenylbutyl(aminocarbonyl)methylcarbamate.
 22. The compound or pharmaceuticallyacceptable salt according to claim 14, wherein the compound is asubstantially pure stereoisomer.
 23. The compound or pharmaceuticallyacceptable salt according to claim 22, which is selected from the groupconsisting of: (2R)-2-amino-3-phenylpropyl(aminocarbonyl)methylcarbamate; (2R)-2-(dimethylamino)-3-phenylpropyl(aminocarbonyl)methylcarbamate; (2R)-2-amino-3-phenylpropyl(aminocarbonyl)benzylcarbamate; (2R)-2-amino-3-phenylpropyl(aminocarbonyl)ethylcarbamate; (2R)-2-amino-3-(2-chlorophenyl)propyl(aminocarbonyl)methylcarbamate; (2R)-2-amino-3-(4-chlorophenyl)propyl(aminocarbonyl)methylcarbamate;(2R)-2-amino-3-(2,4-dichlorophenyl)propyl(aminocarbonyl)methylcarbamate;(2R)-2-amino-3-(3,4-dichlorophenyl)propyl(aminocarbonyl)methylcarbamate; (2S)-2-amino-3-phenylpropyl(aminocarbonyl)methylcarbamate; (2R)-2-amino-3-(4-nitrophenyl)propyl(aminocarbonyl)methylcarbamate; (2R)-2-amino-3-(4-methylphenyl)propyl(aminocarbonyl)methylcarbamate; (2R)-2-amino-3-(4-ethoxyphenyl)propyl(aminocarbonyl)methylcarbamate; and (2R)-2-amino-4-phenylbutyl(aminocarbonyl)methylcarbamate.
 24. The compound or pharmaceuticallyacceptable salt according to claim 14, wherein the salt ishydrochloride.
 25. A pharmaceutical composition comprising atherapeutically effective amount of the compound or pharmaceuticallyacceptable salt of claim 1 and a pharmaceutically acceptable carrier.26. The pharmaceutical composition of claim 25, which is an oralformulation.
 27. The pharmaceutical composition of claim 25, furthercomprising an active ingredient which is effective to treat ADHD.
 28. Amethod of treating a dopamine reuptake-related disease, comprising:administering a therapeutically effective amount of the compound orpharmaceutically acceptable salt of claim 1 to a mammal in need thereof.29. The method according to claim 28, wherein the dopamine-relateddisease is attention deficit hyperactivity disorder (ADHD).